Project Summary/Abstract Among head and neck cancer (HNC) patients, 92% report fatigue and 73% have pain. A 10% increase in fatigue or pain is associated with a 10-25% reduction in HNC survival. During the critical transition period from the end of active treatment to 3 months post-treatment (during which patients begin symptom self- management), untreated physical symptoms negatively impact functional status (ADL) and quality of life (QOL). Fatigue and musculoskeletal pain (related to tissue damage from surgery and radiation) are known to improve in response to physical activity (PA). However, 51% of HNC survivors rarely engage in any type of PA because of complicated PA barriers: impaired fitness, severe physical symptoms, and poor PA health beliefs. A critical gap in our science is that no home-based behavioral PA intervention effectively addresses these PA barriers in HNC patients. To address this gap, our overall objective is to test an intervention to overcome these PA barriers for HNC patients during the critical transition period to self-management. PAfitME, a personalized Physical Activity intervention with fitness graded Motion Exergames, is a telehealth program built on Social Cognitive Theory and the exercise principal of adaptation. PAfitME is personalized to the HNC patient's PA barriers. PAfitME, delivered via a tested mix of FaceTime calls and home visits, uses commercially available exergaming platforms (Wii Fit and Xbox Kinect). Our pilot study generated impressive within-group effect sizes for fatigue, pain, and ADL (d?0.9). The feasibility and acceptability of PAfitME were also strong in patients with several physical limitations. Attendance (98%) and attrition (20%) were much better than previous HNC studies without adverse events. We propose the following specific aims: (1) When compared to an attention control group, determine the effect of PAfitME on fatigue and musculoskeletal pain at week 6, when controlling for age and sex; (2) when compared to an attention control group, determine the effect of PAfitME on functional status and QOL at week 6, when controlling for age and sex; and (3) explore if PA self-efficacy, PA enjoyment, and exergame minutes mediate the effect of PAfitME on fatigue and musculoskeletal pain. This study will evaluate 150 post-treatment (radiation or chemoradiation) HNC patients in an RCT with an attention control. For 6 weeks, the experimental (PAfitME) group will receive the PAfitME intervention, and the attention control group will receive NCI-based survivorship education and exergame equipment (Wii Fit or Xbox Kinect without PAfitME). For Aims 1 and 2, using an ITT framework, we will fit a series of linear mixed effects models with each of the outcome variables. For Aim 3, we will conduct our exploratory analyses in ml_mediation (STATA 15), which will compute direct and indirect effects for multi-level data. This study aligns with the NCI Cancer Moonshot goal to minimize cancer treatment-associated side effects and the key recommendation in the National Comprehensive Cancer Network Clinical Guidelines of the need for evidence-based non- pharmacological fatigue/pain treatments (National Priority).